tbuckley/cabot-search huggingface dataset:
Outcomes in high-grade neuroendocrine carcinomas (HG-NEC) of the gastrointestinal (GI) tract with modern therapies.
Authors: Erika Belmont, Koosha Paydary, Chih-Yi Liao, Blase N. Polite, Hedy L. Kindler, Namrata Setia, Ardaman Shergill
Journal: Journal of Clinical Oncology (2022)

e15609 Background: HG-NEC of the GI tract are rare and aggressive neoplasms with poor prognosis. Approximately 37.5% of extra-pulmonary NEC are of the GI origin and are most commonly located in esophagus, stomach, pancreas and colon (1,2). Median survival of 7.5 months, with range of 5.7 months to 25.1 months has been reported (2). However, data regarding response to immunotherapy, as well as response to molecularly directed therapies are sparse. In this study, we conducted a retrospective review of GI tract HG-NEC with objective to assess role of modern diagnostics and therapies in clinical outcomes. Methods: We identified 14 patients with GI tract HG-NEC who received care at University of Chicago Medical Center (UCMC). Electronic medical records were reviewed for disease stage, treatments and clinical course. We reviewed available next generation sequencing (NGS) and circulating tumor DNA (ct-DNA) test results. In this cohort, UCMC’s NGS panel: Oncoplus was available and Guardant 360 results were reviewed for liquid biopsy. Results: In our initial review, site of origin included right side of colon (46%), left sided colon (46%), and anus/anorectal (15%). Median overall survival (mOS) ranged from 1.3 months to 81.3 months, and notably the median response to chemo-immunotherapy (IO) was 7.9 months (table 1). Notably one patient received maintenance therapy with immunotherapy alone with progression of disease (POD) in 3 weeks. Six patients had NGS results of which three (50%) had therapeutic targetable alterations (Table). Two patients had liquid biopsy done, of which one had targetable alterations and the other had no tumor related alterations detected. Of the two patients with targetable lesions, one patient has received targeted therapy with POD in 1.2 months and median OS 8.8 months; the other is in the process of initiating targeted therapy. Conclusions: To our knowledge, this is the first report to show a response to combination chemo-immunotherapy and targeted therapies in HG-NEC of GI tract. We are collaborating with other institutions to collate outcomes to similar therapy approaches in this patient cohort. With our study, we hope to inform future therapies and innovation in this important disease.
Re-induction with venetoclax in combination with hypomethylating agents (HMAs) versus FLAG-IDA in relapsed or refractory AML.
Authors: Ian Michael Bouligny, Keri Renee Maher
Journal: Journal of Clinical Oncology (2022)

e19030 Background: The optimal selection and sequence of salvage regimens during treatment of acute myeloid leukemia (AML) remains unclear. While venetoclax augmentation of a hypomethylating agent backbone is now routinely used as salvage following impressive performance in the front-line setting, little is known about outcomes in relapsed or refractory AML, especially when compared to re-inductions with anthracycline-based regimens. Thus, the aim of this study was to compare outcomes of venetoclax-based regimens versus FLAG-IDA in patients under 70 years. Methods: We retrospectively analyzed 47 patients with AML that were younger than 70 years in the relapsed and refractory setting treated with either FLAG-IDA (fludarabine, cytarabine, G-CSF, and idarubicin) or venetoclax in combination with decitabine or azacitidine from July 2017 to December 2020. Two cohorts were created: a FLAG-IDA cohort and a matched venetoclax cohort for age, ECOG score, and comorbidities. Cytogenetic risk and molecular profiling (through next-generation sequencing [NGS]) at diagnosis and throughout treatment, dates and doses of induction, toxicity, responses, and measurable residual disease (MRD) analysis were recorded and analyzed. Results: In the venetoclax cohort of 32 patients, the median age was 60 years, the median ECOG score was 1, and the median Charlson Comorbidity Index (CCI) score was 4. Six out of 22 evaluable patients achieved either a CR or CRi for a composite response rate (CRR) of 27.3%. Out of three evaluable patients that responded, none were MRD-negative by NGS. The overall survival (OS) of the venetoclax cohort was 8.2 months. In the FLAG-IDA cohort of 15 patients, there were no statistical differences between age (p = .114), ECOG score (p = .249), or CCI score (p = .137) compared to the venetoclax cohort. The CRR of the FLAG-IDA cohort was 85.7%, a significant difference from the venetoclax cohort (p = .011), and 50% were negative for MRD by either NGS or PCR. The overall survival was not reached at a median follow-up time of 15.5 months, significantly different compared to the venetoclax cohort by the log-rank test (p = .001). A Cox proportional hazards model was used to investigate the effects of commonly mutated genes ( NPM1, ASXL1, FLT3, IDH1/2, RAS, TP53, TET2) on OS in venetoclax-based re-induction, and identified IDH1/2 mutations as having a favorable impact in the relapsed/refractory setting (HR 0.01, 95% CI 0.0001-0.7214). Conclusions: Our results highlight the efficacy of FLAG-IDA compared to venetoclax-based regimens with respect to CRR and survival, significantly favoring FLAG-IDA at the time of relapsed or refractory disease. Although limited by sample size, IDH1/2 mutations may convey a better prognosis in the relapsed/refractory setting when treated with venetoclax + HMAs. Larger studies are needed to confirm these findings.
Dostarlimab in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC): The GARNET study.
Authors: Ana Oaknin, Bhavana Pothuri, Lucy Gilbert, Renaud Sabatier, SharadA. Ghamande, Adriano Gravina, Emiliano Calvo, SusanaN. Banerjee, Rowan Miller, Joanna Pikiel, MansoorRaza Mirza, Tao Duan, Sybil Zildjian, Eleftherios Zografos, JenniferLynnTaylor Veneris, Anna Tinker
Journal: Journal of Clinical Oncology (2022)

5509 Background: Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the U.S. as a monotherapy in patients (pts) with dMMR AR EC that has progressed on or after treatment with a platinum-containing regimen or dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options; and in the E.U. as a monotherapy in pts with dMMR/MSI-H AR EC that has progressed on or after treatment with a platinum-containing regimen. Here, we report on efficacy and safety in the 2 expansion cohorts of the GARNET trial that enrolled pts with EC. Methods: GARNET is a multicenter, open-label, single-arm phase 1 study. Pts were assigned to cohort A1 (dMMR/MSI-H EC) or cohort A2 (MMRp/MSS EC) based on local assessment. Pts received 500 mg of dostarlimab IV Q3W for 4 cycles, then 1,000 mg Q6W until disease progression, discontinuation, or withdrawal. The primary endpoints are ORR and DOR by blinded independent central review using RECIST v1.1. Results: For this third interim analysis, 153 dMMR/MSI-H and 161 MMRp/MSS pts were enrolled and dosed. Of these, 143 dMMR/MSI-H and 156 MMRp/MSS pts had measurable disease at baseline and ≥ 6 mo of follow-up and were included in the efficacy-evaluable population. ORRs were 45.5% (dMMR/MSI-H) and 15.4% (MMRp/MSS; Table). Median (m) DORs were not reached (NR; dMMR/MSI-H) and 19.4 mo (MMRp/MSS). Probability of PFS at 6, 9, and 12 mo was 49.5%, 48.0%, and 46.4% in dMMR/MSI-H EC and 35.8%, 31.3%, and 29.4% in MMRp/MSS EC, respectively. mOS was NR (dMMR/MSI-H) and 16.9 mo (MMRp/MSS). Overall, 27 pts (8.6%) discontinued treatment because of a treatment-related adverse event (TRAE; 13 dMMR/MSI-H, 14 MMRp/MSS). The majority of TRAEs were grade 1 or 2. The most common any-grade TRAEs were fatigue (56; 17.8%), diarrhea (46; 14.6%), and nausea (43; 13.7%). No deaths were attributed to dostarlimab in the EC cohorts. Hypothyroidism (12; 8%) was the most common any-grade immune-related TRAE. Conclusions: Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H and MMRp/MSS AR EC. dMMR/MSI-H was associated with better outcomes: a higher response rate and longer PFS and OS. Safety was consistent with other PD-1 antibodies. Clinical trial information: NCT02715284. [Table: see text]
Clinical utility of circulating tumor DNA sequencing with a large panel in patients with advanced soft-tissue sarcomas.
Authors: Julie Blanchi, Sofiane Taleb, Arnaud Bayle, Benjamin Verret, Maud Toulmonde, Mariella Spalato, Melissa Alame, Emmanuel Khalifa, Antoine Italiano
Journal: Journal of Clinical Oncology (2022)

11550 Background: Preliminary studies have suggested that the detection, quantification, and profiling of ctDNA in patients with sarcoma is feasible and may improve prognostication, measure treatment response, and detect relapse. However, data related to impact of ctDNA profiling to tailor therapy in patients with advanced disease are lacking. Methods: Patients with advanced soft-tissue sarcomas (STS) have been included in two ongoing institutional molecular profiling studies (BIP: NCT02534649, STING: NCT04932525). Genomic analysis (ctDNA in all cases and tissue when available) was performed by using the Foundation One Liquid CDx Assay (324 genes, tumor mutational burden [TMB], microsatellite instability status). Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumour board dedicated to precision medicine, attended by experts in clinical oncology, molecular biology, and clinical genetics. Actionable targets were defined by the MTB according to the existing level of evidence (ESCAT), and molecular-based treatment suggestions were proposed where possible. Results: Between December 2020 and August 2021, 98 patients with metastatic STS underwent ctDNA profiling. Median time to assay results was 12 days. Results were contributive for 86 patients (88%). At least one actionable target (range 1-4) was detected in 35 patients (36%) including high tumor mutational burden (&gt; 16 mutations/Mb) for 1 patient (1%) and alteration of the DNA repair response pathway for 12 patients (12%). Overall, the MTB recommended a matched therapy for 27 patients (28%). 40 patients underwent also NGS of tissue besides ctDNA profiling. The number of actionable alterations was similar in 26 (65%), whereas it was higher in tissue for 10 (25%) and in liquid for 4 (10%) patients. Conclusions: This large-scale study demonstrates that liquid biopsy with a large NGS ctDNA panel is an efficient approach to match patients to genomically directed clinical trials/targeted therapies in patients with advanced STS. Outcomes of patients treated with matched therapy will be presented at the meeting.
Nodule vascularity as novel radiomics imaging endpoint for lung cancer diagnosis and prognosis.
Authors: François Blistein, Sebastien Goffart, Flore Belmans, Ingrid van Peufflik, Sean Walsh, Mariaelena Occhipinti, Wim Vos, Akshayaa Vaidyanathan
Journal: Journal of Clinical Oncology (2022)

e20580 Background: The vascularization of lung nodules has been proven as severe risk factor for malignancy, and in lung cancer, indication of worse prognosis (1,2). For this reason, we developed a novel imagining endpoint based on the vasculature surrounding a lung mass and we tested this endpoint for the prediction of malignancy for lung nodules. Methods: The vasculature of the nodules (both arteries and veins) has been computed using the surface intersection between the nodule and the vascular structure 3D meshes. Both 3D structures were obtained by converting the segmentations of the nodule and of the vessels to meshes with a marching cubes algorithm. Nodule and vessels segmentation has been obtained with an in-house deep learning segmentation model. The features considered are the numbers of intersections, the total area of intersection and the mean area of intersection. These features have been used to predict nodule malignancy on thoracic CT scans from the Lung Image Database Consortium image collection (3). Quality controls on clinical data completeness and imaging parameters resulted in a cohort of 894 scans (715 for training and 179 for testing), from the original 1018 cases. The malignancy status is defined as high risk and low risk, based on the consensus classification of a panel of four radiologists. Firstly, an univariate analysis is performed to assess the variability of the features grouped by the malignancy score by using Mann-Whitney and ANOVA tests. After, seven combinations of features have been used to train generalized linear models (GLM) to predict nodule malignancy. To compare the models, the Area Under the Curve (AUC) is used as the main performance metric. Results: Univariate analysis of each feature grouped by the malignancy outcome showed that all the three features have good univariate discriminative power between high risk and low risk categories ( p value ≤ 0.05), with nb_connections as the most predictive singular feature ( p value of 1.343277 × 10 -36 ). All the GLM models developed showed a good performance (AUC equal or higher than 0.7), with the best model in testing based on the combination of mean_area and sum_area (AUC of 0.84). Conclusions: The radiomics vascularity endpoint has been proven capable of predicting nodule malignancy with very good performance. The singular feature that is most related to malignancy is the number of vessels intersecting the nodule while the total area of intersection followed by the number of intersections are the most useful to model risk of malignancy. Wang et al., Lung Cancer 114: 38–43, 2017. Hamanaka et al., Diagn Pathol 10,17, 2015. G. Armato et al., Med. Phys., 38: 915-931, 2011.
ChosenHRDw: A novel tool for the detection of homologous recombination deficiency(HRD) using low-pass whole-genome sequencing.
Authors: Xiaotian Zhang, Weiwei Tian, Yakun Wang, Wang Bing, Chen Pengyan, Hu Yukai, Yiqun Zhang, Wu Cheng, Huang Xiumin, Qianhui Wan, Shi Xinying, Zhihua Pei, Zhou Qiming, Dongliang Wang, Lin Shen
Journal: Journal of Clinical Oncology (2022)

e17573 Background: Homologous recombination deficiency(HRD) as a promising biomarker holds predictive and prognostic value in anticancer therapies, especially in ovarian cancer. Although next-generation sequencing techniques such as whole-exome sequencing (WES) and targeted sequencing have proven to be powerful detection of HRD, the latest low-pass (1x) whole-genome sequencing (WGS) with characteristic large-scale patterns for HRD detection status, as a cost-effective screening strategy, have established feasibility. In this study, we developed the ChosenHRDw, a comprehensive algorithm, which utilizing low-pass WGS to effectively classify the HRD status by defining the high or low HRD score. Methods: In this work, a correction method base on GC-content was applied. Then we took a window size of 1Mb resolution, and removed the error alignments genome bins basing on the healthy cohort data. Baseline of each bins was constructed from the data of 100 healthy volunteers. We characterized and quantified 8 HRD-related signatures: LOH score, TAI score, LST score, chromosomal instability index(CIN index), wGII(weighted genome instability index), CNV ratio (copy number ratio in bins), HRR index (HRR gene instability index), TFBS ratio (copy number ratio in transcription factor binding sites) as the variables in a random forest model. Results: A total of 140 patients (pts) were enrolled in the discovery cohort, which including 70 high HRD score and 70 low HRD pts were confirmed by HRDetect on paired tumor/normal samples via 1123plus-genes panel targeted sequencing. The AUC was 0.93. Independent validation was conducted in a validation cohort of 60 pts, which HRD high or low pts were 30 and 30, respectively. The sensitivity = 0.87 and specificity = 0.9. Conclusions: We classified HRD into high vs low using ChosenHRDw, which showing strong concordance. Our analyses demonstrated that the prediction of HRD status can be achieved from low-pass WGS. Due to the limitation of relatively small sample size, real-world studies with a larger number of patients are needed to verify our algorithm in the future.
Characterization of URST1 as a biomarker and therapeutic target for oral cancer.
Authors: Atsushi Takano, Yoshihiro Yoshitake, Masanori Shinohara, Yataro Daigo
Journal: Journal of Clinical Oncology (2022)

e18092 Background: Cancer-specific oncoproteins are expected to be useful for the development of novel biomarkers and therapeutic targets for oral cancers. Methods: We screened candidate oncoproteins as follows: i) Identification of up-regulated genes in oral cancers by gene microarray, ii) Validation of clinicopathological significance of their protein expression by tissue microarray, iii) Examination of their growth effect on cancer cells by siRNA/small molecule compounds, iv) Elucidation of their tumor promoting effects by enforced gene expression. Results: Using above mentioned approach, we identified URST1 (Up-regulated solid tumor 1) as a candidate. Immunohistochemical staining showed that URST1 protein expression was observed in 110 (71.0%) of 155 oral cancers that had undergone curative surgery. In addition, high level of URST1 expression was associated with poor prognosis for oral cancer patients ( P = 0.0021, by log-rank test) and it was an independent prognostic factor. Reduction of URST1 expression by siRNA specific for URST1 significantly suppressed the growth of oral cancer cell lines and induced G2/M arrest as detected by flowcytometry and time lapse imaging. In contrast, enforced expression of URST1 enhanced the growth of oral cancer cells. The growth of oral cancer cells were inhibited by the URST1 inhibitor. Microarray analysis coupled with siRNAs for URST1 suggested various URST1-related oncogenic pathways in oral cancer cells. Conclusions: URST1 is a possible prognostic biomarker and therapeutic target for oral cancer.
A first-in-human phase I dose escalation of YH001, an anti-CTLA-4 monoclonal antibody (mAb), in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.
Authors: Vinod Ganju, Adam Cooper, Bo Gao, Kate Wilkinson
Journal: Journal of Clinical Oncology (2022)

2602 Background: YH001 is a humanized anti-hCTLA-4 IgG1 mAb that relieves CTLA-4-mediated immunosuppression, and thereby enhances the T-cell-mediated antitumor immune response. Pre-clinical data have shown potent anti-cancer activity when combined with anti-PD-1 mAb. Methods: This is an ongoing phase 1 dose-escalation study conducted in Australia. Patients (pts) with advanced solid tumors received YH001 by IV administration at 0.05 to 6.0 mg/kg for 1 cycle (21 days) then in combination with Toripalimab (anti-PD-1 mAb) at 240 mg Q3W for 4 cycles. An accelerated titration method followed by the standard "3+3" design was utilized to evaluate safety, tolerability and preliminary efficacy. Results: As of 31-Dec-2021 data cut-off, 24 pts with advanced solid tumors were enrolled and dosed at 0.05 mg/kg (n=2), 0.1 mg/kg (n=3), 0.3 mg/kg (n=3),1mg/kg (n=5), 2mg/kg (n=5), 4mg/kg (n=3) and 6mg/kg (n=3). Baseline ECOG scores were 0 (n=14), 1 (n=10) with all pts progressed after a median of 2 prior lines of available standard therapy (range 1-5) including 5 pts progressed after prior immunotherapy of anti-PD-1 antibody. Overall, 6 cases of Grade(G) 3 or above treatment-related AEs (TRAEs) have been reported in 5 pts at 0.3 mg/kg, 4 mg/kg and 6 mg/kg dose level respectively, including 1 G3 colitis, 1 G4 thrombocytopenia, 1 G3 Enterocolitis, 1 G3 Rash, 1 G3 Pruritus and 1 G3 hepatitis. There were no death events due to TRAEs. 18 pts (75%) had 63 TRAEs of any level, including 28 G1 TRAEs, 29 G2 TRAEs. 2 of the first 3 pts at MAD (6mg/kg) met protocol defined DLT in Combo phase. Among the 23 pts having imaging tumor assessment by RECIST v1.1, 4 achieved PR and 9 achieved SD in Best of Response. 1 subject with gastroesophageal junction carcinoma at 0.3 mg/kg has achieved PR since the 2 nd tumor assessment, target lesion decreased by up to 84.5% from baseline. 1 subject with urothelial carcinoma at 2 mg/kg progressed after prior anti-PD-1 antibody has achieved PR since the 2 nd tumor assessment, target lesion decreased by up to 74% from baseline. 1 subject with uterine carcinosarcoma at 2 mg/kg has achieved PR since the 1 st tumor assessment, target lesion decreased by up to 52.3% from baseline. 1 subject with vulva adenocarcinoma at 6 mg/kg has achieved PR since the 1 st tumor assessment, target lesion decreased by up to 71.4% from baseline. ORR (CR+PR) and DCR (CR+PR +SD) were 17.4%, 56.5% respectively. Conclusions: YH001 was well tolerated up to 4 mg/kg dose levels when combined with toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04357756.
ARTISTRY-3: Effect of nemvaleukin alfa with a less frequent IV dosing schedule as monotherapy and in combination with pembrolizumab and impact on the tumor microenvironment (TME) in patients (pts) with advanced solid tumors.
Authors: Sarina Anne Piha-Paul, Corrine F. Elliott, Yangchun Du, Julie R. Graham, Monali Desai, MD, Yan Wang, Rita P. Dalal, Nehal J. Lakhani
Journal: Journal of Clinical Oncology (2022)

TPS2684 Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokine that selectively binds the intermediate-affinity interleukin-2 (IL-2) receptor, preferentially activating and expanding antitumor CD8 + T cells and NK effector cells, with minimal effect on regulatory T cells. Nemvaleukin was designed to leverage antitumor effects of the IL-2 pathway while limiting typical IL-2‒associated toxicity. In ARTISTRY-1, the recommended phase 2 dose (RP2D) for nemvaleukin monotherapy of 6 µg/kg IV on days 1 to 5 of a 21-day cycle elicited durable and deep responses in pts with advanced melanoma and renal cell carcinoma (Boni et al. ASCO 2021:abstr 2513). Responses with nemvaleukin plus pembrolizumab were also observed in platinum-resistant ovarian, breast, cervical, gastrointestinal, and genitourinary cancers. ARTISTRY-3 will investigate the effects of nemvaleukin as monotherapy and in combination with pembrolizumab on the TME in pts with advanced solid tumors, and in an additional cohort (Cohort 2), to further assess a less frequent IV dosing schedule for nemvaleukin. Methods: The phase 1/2, open-label ARTISTRY-3 (NCT04592653) study will enroll adults (≥18 years) with select advanced solid tumors, ≥1 accessible lesion for biopsy, ≥1 target lesion (per RECIST v1.1), ECOG PS of 0 or 1, estimated life expectancy of ≥3 months, adequate hematologic reserve, and adequate hepatic and renal function. Primary objectives: to evaluate effects of nemvaleukin monotherapy on the TME (Cohort 1) and to determine RP2D for less frequent dosing schedule (Cohort 2). Additional objectives are to evaluate: efficacy, safety, immunogenicity, and pharmacokinetics of nemvaleukin monotherapy; effects of nemvaleukin plus pembrolizumab on the TME; and correlative biomarkers of nemvaleukin as monotherapy and combination. Following the protocol amendment, additional pts enrolled in Cohort 1 will receive lead-in monotherapy at a dose selected based on results from Cohort 2, and pre- and on-treatment biopsies will be collected for TME assessments. Subsequent cycles will be administered in combination with pembrolizumab, and a biopsy may be collected at cycle 4 or 5. Tumor types eligible for Cohort 2 are selected based on activity observed in the ARTISTRY-1 study. A quantitative system pharmacology model was applied to identify a less frequent schedule for nemvaleukin monotherapy and combination. Cohort 2 will initially assess safety and tolerability of nemvaleukin at 1 dose per 21-day cycle. Two doses per 21-day cycle may be implemented to achieve optimal PK/PD parameters. Bayesian optimal interval design methodology with open enrollment will be applied to facilitate dose escalation decisions. Clinical trial information: NCT04592653.